The general notion of using mixtures or combinations of collagen protein and bone minerals in effecting hard tissue repair has been known for some time. As bone itself is comprised of these minerals, along with collagen, it seemed promising to utilize this combination. However, implementation of this concept has not proved to be as simple as might have been supposed. First, it has been difficult to obtain a preparation which has the correct physical properties to provide a support matrix for bone in-growth so as to result in a successful repair. Second, unless the proteinaceous component was derived from tissue of the same individual who is the recipient of the implant, inflammatory responses are commonplace as a result of the immunogenic character of the implant. This problem is not entirely obviated by using collagen derived from the same species, but performance is improved over that resulting from use of collagen from, for example, bovine or porcine sources in humans. Thus, the form of the collagen used is critical to the success of the implant. The form of the mineral component is not critical, except the resulting mixtures must have handling properties suitable for the indications.
Reports of attempts to use the collagen/mineral combination are numerous. For example, Lemons, J., et al., reported at the Second World Congress of Biomaterials in Washington, D.C., 27 Apr.-1 May 1984, on attempts to utilize collagen along with commercial hydroxyapatite and calcium phosphate to repair artificially created lesions in rabbits. The use of these mixtures did not result in reunion of the lesions. A control experiment using fresh autogenous bone, however, was successful in producing a union. Similarly, Levy, P., et al, J Periodontal (1981), :303-306, were unsuccessful in their attempts to utilize collagen/mineral gel implants to repair intra-bony defects in root canals of canine or monkey teeth. Gross, B. C., et al., Oral Surg (1980), 49:21-26, reported limited success in using mixtures of reconstituted lyophilized calfskin collagen in admixture with a hydroxyapatite preparation to induce bone growth through subperiosteal implants in monkeys. Various others have reported use of forms of collagen which clearly contain telopeptides, a major source of immunogenicity of collagen, in combination with minerals in bone repair. See, for example, Hayashi, K. et al., Arch Orthop Traumat Surg (1982) 99:265-269; Battista, U.S. Pat. No. 4,349,490 (using a hydrated gelatin); Cruz, Jr., U.S. Pat. No. 3,767,437 (using a calcium-precipitated form of collagen); and Battista, et al., U.S. Pat. No. 3,443,261; utilizing, in addition to calcium phosphate, a "new form" of collagen which contains microcrystals of aggregated tropocollagen units.
Miyata, et al., U.S. Pat. No. 4,314,380, utilized a mineral backbone prepared directly by treatment of animal bone to remove all organic materials, which was then coated with an atelopeptide collagen. Japanese Application No. J58/058041, published 6 Apr. 1983, discloses a spongy porous calcium phosphate material having pores treated with atelopeptide collagen. The collagen derives from collagen-in-solution having a concentration of not more than 2% by weight. The Japanese application reports the advance of osteoblasts into the pores of the material and new bone growth. European Patent Application, Publication No. 030583, published 24 Jun. 1981, discloses use of Collagenfleece.RTM. in admixture with hydroxyapatite in bone repair. This collagen material is a commercial product, is obtained from animal hide by proteolytic digestion, and is lyophilized and sterilized by gamma irradiation. This collagen preparation forms a soft membrane-like material but does contain telopeptides and is partially degraded by the processing.
In summary, there have been numerous attempts to use combinations of calcium phosphate mineral components and collagen in various forms of bone defect repair with mixed success. It is clear that the art contains no perfect composition which can be relied upon to provide satisfactory results in a predictable manner in connection with a specific process. A reproducibly effective preparation for encouraging bone in-growth was, until the present invention, lacking in the art.